N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as a2a agonists

ABSTRACT

The present invention provides N-alkyl 2-(disubstituted)alkynyladenosine-5′-uronamides and derivatives thereof and pharmaceutical compositions containing the same that are selective agonists of A 2A  adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.

FIELD OF THE INVENTION

The present invention relates to N-Alkyl 2-(disubstituted)alkynyladenosine-5′-uronamides and pharmaceutical compositions that areselective agonists of A_(2A) adenosine receptors (ARs). These compoundsand compositions are useful as pharmaceutical agents.

BACKGROUND OF THE INVENTION

Adenosine A_(2A) receptors (also known as ADORA2A) are members of the Gprotein-coupled receptor (GPCR) family which possess seven transmembranealpha helices. The receptor is mediated by G proteins, which activateadenylyl cyclase and is abundant in basal ganglia, vasculature andplatelets and is a major target of caffeine. The A_(2A) receptor isresponsible for regulating myocardial blood flow by vasodilating thecoronary arteries, which increases blood flow to the myocardium, but maylead to hypotension. The A_(2A) receptor is also expressed in the brain,where it has important roles in the regulation of glutamate and dopaminerelease. The A_(2A) receptor signals in both the periphery and the CNS,with agonists explored as anti-inflammatory drugs and antagonists asuseful in neurodegenerative disorders such as Parkinson's disease.

Despite the increasing development of adenosine A_(2A) receptoragonists, as described above, only one, regadenoson, an adenosineanalog, has been approved for use in the United States as a coronaryvasodilator. Typical issues involved with administration of thesecompounds include side effects due to the wide distribution of adenosinereceptors, low brain penetration (which is important for the targetingof CNS diseases), short half-life of compounds, and/or a lack ofeffects, in some cases possibly due to receptor desensitization or toolow receptor density in the targeted tissue. Therefore, it is importantto continue to synthesize and test additional A_(2A) receptor agonistsin order to develop new and improved therapeutic agents.

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novel N-alkyl2-(disubstituted)alkynyladenosine-5′-uronamides or pharmaceuticallyacceptable salts thereof that are A_(2A) agonists.

In another aspect, the present invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides methods of treating apathological condition or symptom in a mammal for which the A_(2A)receptor is implicated (e.g., an adenosine A_(2A) receptor associatedstate, such as glaucoma or ocular hypertension) and agonism of thereceptor provides therapeutic benefit by administering to a subject aneffective amount of an adenosine A_(2A) receptor agonist of the presentinvention or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides methods of treatingand/or preventing an adenosine A_(2A) receptor-associated state in asubject by administering to the subject an effective amount of anadenosine A_(2A) receptor agonist of the present invention or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides adenosine A_(2A)receptor agonists for use in medical therapy.

In another aspect, the present invention provides the use of adenosineA_(2A) receptor agonists of the present invention for the manufacture ofa medicament for the treatment of a pathological condition or symptom ina mammal for which the A_(2A) receptor is implicated (e.g., an adenosineA_(2A) receptor associated state, such as glaucoma or ocularhypertension) and agonism of the receptor provides therapeutic benefit.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed compounds or pharmaceutically acceptable saltforms thereof are expected to be effective A_(2A) agonists.

DETAILED DESCRIPTION OF THE INVENTION

All references cited herein are hereby incorporated in their entiretyherein by reference.

In an aspect, the present invention provides novel compounds of FormulaI or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R is selected from: C₁₋₈ alkyl and C₃₋₈ cycloalkyl;

R¹ is independently selected from: H, C₁₋₈ alkyl, and C₃₋₈ cycloalkyl;

q is 1;

r is independently selected from 0, 1, 2, 3, 4 and 5;

R² is selected from: H, C₁₋₈ alkyl, C₃₋₈ cycloalkyl-C₀₋₈alkylene-,C₁₋₈alkoxy-C₁₋₈ alkylene-, 5-10 membered heterocyclyl-C₀₋₈alkylene-,5-10 membered heteroaryl-C₀₋₈ alkylene-, and aryl-C₀₋₈ alkylene-;

alternatively, q is 0, r is 1, and R² is —C(O)—R^(2A);

R^(2A) is selected from: C₁₋₈ alkyl, C₃₋₈ cycloalkyl-C₀₋₈alkylene-,C₁₋₈alkoxy-C₁₋₈ alkylene-, 5-10 membered heterocyclyl-C₀₋₈alkylene-,5-10 membered heteroaryl-C₀₋₈ alkylene-, and aryl-C₀₋₈ alkylene-;

ring A is a phenyl ring or a 5-6 membered heteroaryl attached via thecarbon atom shown and having 1-3 ring heteroatoms selected from O, N,and S(O)_(p);

ring A is optionally substituted with 1-3 R³ groups;

R³ is independently selected from: C₁₋₈ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), OC(O)R^(a), OCO₂R^(a), OC(O)NR^(a)R^(b), NR^(b)COR^(a),NR^(b)CO₂R^(a), NR^(b)C(O)NR^(a)R^(b), S(O)_(p)NR^(a)R^(b),C₃₋₁₀cycloalkyl-C₀₋₈alkylene-, 5-10 membered heterocyclyl-C₀₋₈alkylene-, aryloxy, aryl-C₀₋₈ alkylene-, and 5-10 memberedheteroaryl-C₀₋₈alkylene-;

R^(a) is independently selected from: H, C₁₋₈ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-;

R^(b) is independently selected from: H, C₁₋₈ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-;

n is independently selected from: 1, 2, 3, 4, 5, and 6; and,

p is independently selected from: 0, 1, and 2.

In another aspect, the present invention provides a novel compound ofFormula Ia, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

wherein:

R is selected from: C₁₋₄ alkyl and C₃₋₆ cycloalkyl;

R¹ is selected from: H and C₁₋₄ alkyl;

R² is selected from: H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₀₋₂ alkylene-, andC₁₋₄ alkoxy-C₁₋₄ alkylene-;

ring A is selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, andpyridazinyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-;

R^(b) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-; and,

p is independently selected from: 0, 1, and 2.

In another aspect, the present invention provides a novel compound ofFormula Ia, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: H, methyl, ethyl, isopropyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclobutyl-methylene, cyclopentyl,and methoxy-ethylene;

ring A is selected from: phenyl, pyridyl, and thienyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H and C₁₋₄ alkyl;

R^(b) is independently selected from: H and C₁₋₄ alkyl; and,

p is independently selected from: 0, 1, and 2.

In another aspect, the present invention provides a novel compound ofFormula Ia, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is selected from: phenyl, pyridyl, and thienyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, —CN, OR^(a), CF₃,and OCF₃;

R^(a) is independently selected from: H and C₁₋₄ alkyl; and,

R^(b) is independently selected from: H and C₁₋₄ alkyl.

In another aspect, the present invention provides a novel compound ofFormula Ia, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is phenyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ia, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 3-pyridyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ia, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 4-pyridyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ia, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 2-thienyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein: the compound is selected from a compound of Table 1.

In another aspect, the present invention provides a novel compound ofFormula Ib, or a stereoisomer or pharmaceutically acceptable saltthereof:

wherein:

R is selected from: C₁₋₄ alkyl and C₃₋₆ cycloalkyl;

R¹ is selected from: H and C₁₋₄ alkyl;

R² is selected from: H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₀₋₂ alkylene-, andC₁₋₄ alkoxy-C₁₋₄ alkylene-;

ring A is selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, andpyridazinyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-;

R^(b) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-; and,

p is independently selected from: 0, 1, and 2.

In another aspect, the present invention provides a novel compound ofFormula Ib, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: H, methyl, ethyl, isopropyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclobutyl-methylene, cyclopentyl,and methoxy-ethylene;

ring A is selected from: phenyl, pyridyl, and thienyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H and C₁₋₄ alkyl;

R^(b) is independently selected from: H and C₁₋₄ alkyl; and,

p is independently selected from: 0, 1, and 2.

In another aspect, the present invention provides a novel compound ofFormula Ib, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is selected from: phenyl, pyridyl, and thienyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, —CN, OR^(a), CF₃,and OCF₃;

R^(a) is independently selected from: H and C₁₋₄ alkyl; and,

R^(b) is independently selected from: H and C₁₋₄ alkyl.

In another aspect, the present invention provides a novel compound ofFormula Ib, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is phenyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ib, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 3-pyridyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ib, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 4-pyridyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ib, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 2-thienyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ic, or a stereoisomer or pharmaceutically acceptable saltthereof:

wherein:

R is selected from: C₁₋₄ alkyl and C₃₋₆ cycloalkyl;

R¹ is selected from: H and C₁₋₄ alkyl;

R^(2A) is selected from: C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₀₋₂ alkylene-, andC₁₋₄ alkoxy-C₁₋₄ alkylene-;

ring A is selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, andpyridazinyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-;

R^(b) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-; and,

p is independently selected from: 0, 1, and 2.

In another aspect, the present invention provides a novel compound ofFormula Ic, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R^(2A) is selected from: methyl, ethyl, isopropyl, isobutyl,cyclopropyl, cyclopropyl-methylene, cyclobutyl, cyclobutyl-methylene,cyclopentyl, and methoxy-ethylene;

ring A is selected from: phenyl, pyridyl, and thienyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H and C₁₋₄ alkyl;

R^(b) is independently selected from: H and C₁₋₄ alkyl; and,

p is independently selected from: 0, 1, and 2.

In another aspect, the present invention provides a novel compound ofFormula Ic, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R^(2A) is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is selected from: phenyl, pyridyl, and thienyl;

ring A is optionally substituted with 1-2 R³ groups;

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, —CN, OR^(a), CF₃,and OCF₃;

R^(a) is independently selected from: H and C₁₋₄ alkyl; and,

R^(b) is independently selected from: H and C₁₋₄ alkyl.

In another aspect, the present invention provides a novel compound ofFormula Ic, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R^(2A) is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is phenyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ic, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R^(2A) is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 3-pyridyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ic, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R^(2A) is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 4-pyridyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula Ic, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl;

R¹ is H;

R^(2A) is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene;

ring A is 2-thienyl optionally substituted with 1-2 R³ groups;

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R is selected from: methyl, ethyl, and cyclopropyl.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R¹ is selected from: H and C₁₋₄ alkyl.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R¹ is H.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R² is selected from: H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₀₋₂ alkylene-, andC₁₋₄ alkoxy-C₁₋₄ alkylene-.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R² is selected from: H, methyl, ethyl, isopropyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclobutyl-methylene, cyclopentyl,and methoxy-ethylene.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R² is selected from: methyl, isobutyl, cyclopropyl,cyclopropyl-methylene, cyclobutyl, cyclopentyl, and methoxy-ethylene.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

ring A is selected from phenyl, pyridyl, thienyl, furanyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidyl, andpyridazinyl; and,

ring A is optionally substituted with 1-2 R³ groups.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

ring A is selected from: phenyl, pyridyl, and thienyl; and,

ring A is optionally substituted with 1-2 R³ groups.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

ring A is phenyl optionally substituted with 1-2 R³ groups.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

ring A is 3-pyridyl optionally substituted with 1-2 R³ groups.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

ring A is 4-pyridyl optionally substituted with 1-2 R³ groups.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

ring A is 2-thienyl optionally substituted with 1-2 R³ groups.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-; and,

R^(b) is independently selected from: H, C₁₋₄ alkyl and C₃₋₈cycloalkyl-C₀₋₈ alkylene-.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, Br, I, —CN,OR^(a), SR^(a), NR^(a)R^(b), CF₃, OCF₃, COR^(a), CO₂R^(a),C(O)NR^(a)R^(b), and S(O)_(p)NR^(a)R^(b);

R^(a) is independently selected from: H and C₁₋₄ alkyl; and,

R^(b) is independently selected from: H and C₁₋₄ alkyl.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R³ is independently selected from: C₁₋₄ alkyl, F, Cl, —CN, OR^(a), CF₃,and OCF₃;

R^(a) is independently selected from: H and C₁₋₄ alkyl; and,

R^(b) is independently selected from: H and C₁₋₄ alkyl.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein:

R³ is independently selected from: CH₃, F, Cl, —CN, CF₃, and OCF₃.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein: n is independently selected from: 1 and 2.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein: n is 1.

In another aspect, the present invention provides a novel compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein: one or more H are replaced by D. For example, R¹ canbe D, R² can be D, ring A can be partially or fully substituted with D,the adenosine-uronamide hydrogens can be partially or fully replaced byD. In addition, the groups recited in R, R¹, R², R^(2A), R³, R^(a), andR^(b) that contain a hydrogen (e.g., alkyl, cycloalkyl, alkylene,carbocycle, aryl, heterocycle, and heteroaryl) can be partially or fullyreplaced by D (e.g., CD₃, CD₂CD₃, CD₂CD(CD₃)₂, d₅-cyclopropyl,d₇-cyclobutyl, d₉-cyclopentyl, d₅-cyclopropyl-CD₂, d₅-phenyl, d₄-phenyl(one R³ is present), d₃-phenyl (two R³ are present), d₄-pyridyl,d₃-pyridyl (one R³ is present), and d₂-pyridyl (two R³ are present).

In another aspect, the present invention provides a novel compound ofFormula I, wherein the compound is a deuterium-enriched compound ofI₁-I₁₀ or a stereoisomer or pharmaceutically acceptable salt thereof:

Deuterium-enriched compounds of the present invention can be prepared bya number of known methods including deuterium exchange of acid labilehydrogens (e.g., contacting the compound with NaOD in D₂O) and usingdeuterated starting materials (e.g., deuteratediodo-adenosine-uronamide.

In another aspect, the present invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the present inventionor a pharmaceutically acceptable salt form thereof.

In another aspect, the pharmaceutical composition further comprises ananti-inflammatory compound. Examples of anti-inflammatory compoundsinclude a Type IV phosphodiesterase (PDE) inhibitor or anotheranti-inflammatory compound (e.g., other than a PDE inhibitor). The TypeIV phosphodiesterase inhibitor may be, for example, rolipram,cilomilast, roflumilast, mesembrine, ibudilast, ONO6126, AWD12281,IC485, CP671305, HT0712, or GRC3886.

The present invention further provides novel pharmaceutical compositionsthat include an adenosine A_(2A) agonist in combination with one of moremembers selected from: (a) Leukotriene biosynthes is inhibitors,5-lipoxygenase (5-LO) inhibitors, and 5-lipoxygenase activating protein(FLAP) antagonists selected from the group consisting of zileuton;ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides of Formula (5.2.8);2,6-di-tert-butylphenol hydrazones of Formula (5.2.10); Zeneca ZD-2138of Formula (5.2.11); SB-210661 of Formula (5.2.12);pyridinyl-substituted 2-cyanonaphthalene compound L-739,010;2-cyanoquinoline compound L-746,530; indole and quinoline compoundsMK-591, MK-886, and BAY x 1005; (b) Receptor antagonists forleukotrienes LTB4, LTC4, LTD4, and LTE4 selected from the groupconsisting of phenothiazin-3-one compound L-651,392; amidino compoundCGS-25019c; benzoxazolamine compound ontazolast; benzenecarboximidamidecompound BIIL 284/260; compounds zafirlukast, ablukast, montelukast,pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP45715A), and BAY x 7195; (c) 5-Lipoxygenase (5-LO) inhibitors; and5-lipoxygenase activating protein (FLAP) antagonists; (d) Dualinhibitors of 5-lipoxygenase (5-LO) and antagonists of plateletactivating factor (PAF); (e) Theophylline and aminophylline; (f) COX-1inhibitors (NSAIDs); and nitric oxide NSAIDs; (g) COX-2 selectiveinhibitor rofecoxib; (h) Inhaled glucocorticoids with reduced systemicside effects selected from the group consisting of prednisone,prednisolone, flunisolide, triamcinolone acetonide,beclomethasonedipropionate, budesonide, fluticasone propionate, andmometasonefuroate; (i) Platelet activating factor (PAF) antagonists; (j)Monoclonal antibodies active against endogenous inflammatory entities;(k) Anti-tumor necros is factor (TNFα) agents selected from the groupconsisting of etanercept, infliximab, and D2E7; (l) Adhesion moleculeinhibitors including VLA-4 antagonists; (m) Immunosuppressive agentsselected from the group consisting of cyclosporine, azathioprine, andmethotrexate; or (n) anti-gout agents selected from the group consistingof colchicines.

In another aspect, the present invention provides a novel therapeuticmethod for treating a disease and/or condition in a mammal where theactivity of A_(2A) adenosine receptors is implicated (e.g., an adenosineA_(2A) receptor associated state, such as glaucoma or ocularhypertension) and agonism of these receptors is desired, comprising:administering to a mammal in need thereof a therapeutically effectiveamount of an A_(2A) agonist of the present invention or a stereoisomeror pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a novel therapeuticmethod for treating an adenosine A_(2A) receptor associated state in asubject, comprising: administering to the subject an effective amount ofan A_(2A) agonist of the present invention or a stereoisomer orpharmaceutically acceptable salt thereof.

In another aspect, the adenosine A_(2A) receptor associated state isselected from an autoimmune stimulation (e.g., arthritis, Crohn'sdisease, and chronic obstructive pulmonary disease (COPD)),inflammation, allergic diseases, skin diseases, infectious diseases(e.g., sepsis, Shiga toxin, Clostridium difficile, and Clostridiumdifficile toxin A-induced condition), wasting diseases, organtransplantation, tissue or cell transplantation (e.g., lung, bone marrow(graft versus host disease), kidney, and heart), neuropathic pain, openwounds, adverse effects from drug therapy, a cardiovascular condition,ischemia-reperfusion injury, dialysis, gout, chemical trauma, thermaltrauma, diabetic nephropathy, diabetic foot ulcers, sickle cell disease,laminitis, founder's disease, glaucoma, ocular hypertension, spinalinjury, myocardial infarction, acute myocardial infarction.

In another aspect, the adenosine A_(2A) receptor associated state isselected from: arthritis, Crohn's disease, chronic obstructive pulmonarydisease, sepsis, inflammatory bowel disease, glaucoma, ocularhypertension, diabetic nephropathy, tissue or cell transplantation,

In another aspect, the adenosine A_(2A) receptor associated state isarthritis.

In another aspect, the adenosine A_(2A) receptor associated state isCrohn's disease.

In another aspect, the adenosine A_(2A) receptor associated state ischronic obstructive pulmonary disease.

In another aspect, the adenosine A_(2A) receptor associated state issepsis.

In another aspect, the adenosine A_(2A) receptor associated state isinflammatory bowel disease.

In another aspect, the adenosine A_(2A) receptor associated state isglaucoma or ocular hypertension.

In another aspect, the adenosine A_(2A) receptor associated state isdiabetic nephropathy.

In another aspect, the adenosine A_(2A) receptor associated state istissue or cell transplantation.

In another aspect, the present invention provides the method of treatingan inflammatory disorder, tissue activity or condition, comprising:administering an A_(2A) agonist of the present invention or astereoisomer or pharmaceutically acceptable salt thereof in combinationwith at least one other anti-inflammatory compound (e.g., a Type IV PDEinhibitor).

The inflammatory tissue activity, disorder or condition can be due to(a) pathological agents, (b) physical, chemical, or thermal trauma, or(c) the trauma of medical procedures, such as organ, tissue, or celltransplantation; angioplasty (PCTA); inflammation followingischemia/reperfusion; or, grafting. In yet another embodiment, theinflammatory disorder includes allergen-induced inflammation,ischemia-reperfusion injury, sepsis and autoimmune diseases. Withoutbeing bound by theory, stressed or injured tissues release endogenousadenosine, which blocks potentially destructive inflammatory cascades bybinding to A_(2A) adenosine receptors and decreasing activation ofplatelets, leukocytes and endothelial cells. In these tissues, adenosineacts by reducing expression of adhesion molecules and release ofpro-inflammatory mediators (e.g., reactive oxygen species, elastase andtumor necros is factor-alpha).

Further examples of inflammatory tissue activity or inflammatorydisorders include inflammation due to: (a) autoimmune stimulation(autoimmune diseases), such as lupus erythematosus, multiple sclerosis,infertility from endometriosis, type I diabetes mellitus including thedestruction of pancreatic islets leading to diabetes and theinflammatory consequences of diabetes, including leg ulcers; Crohn'sdisease, ulcerative colitis, inflammatory bowel disease, osteoporos isand rheumatoid arthritis, chronic obstructive pulmonary disease (COPD);(b) allergic diseases such as asthma, hay fever, rhinitis, poison ivy,vernal conjunctivitis and other eosinophil-mediated conditions; (c) skindiseases such as psoriasis, contact dermatitis, eczema, infectious skinulcers, healing of open wounds, cellulitis; (d) infectious diseasesincluding sepsis, septic shock, encephalitis, infectious arthritis,endotoxic shock, gram negative shock, Jarisch-Herxheimer reaction,anthrax, plague, tularemia, ebola, shingles, toxic shock, cerebralmalaria, bacterial meningitis, acute respiratory distress syndrome(ARDS), lyme disease, HIV infection, (TNFα-enhanced HIV replication,TNFα inhibition of reverse transcriptase inhibitor activity), Shigatoxin, Clostridium difficile, and Clostridium difficile toxin A-inducedcondition; (e) wasting diseases: cachexia secondary to cancer and HIV;(f) organ, tissue or cell transplantation (e.g., bone marrow, cornea,kidney, lung, liver, heart, skin, pancreatic islets) includingtransplant rejection, and graft versus host disease; (g) adverse effectsfrom drug therapy, including adverse effects from amphotericin Btreatment, adverse effects from immunosuppressive therapy, (e.g.,interleukin-2 treatment), adverse effects from OKT3 treatment, contrastdyes, antibiotics, adverse effects from GM-CSF treatment, adverseeffects of cyclosporine treatment, and adverse effects of aminoglycosidetreatment, stomatitis and mucositis due to immunosuppression; (h)cardiovascular conditions including circulatory diseases induced orexasperated by an inflammatory response, such as ischemia,atherosclerosis, peripheral vascular disease, restenosis followingangioplasty, inflammatory aortic aneurysm, vasculitis, stroke, spinalcord injury, congestive heart failure, hemorrhagic shock,ischemia/reperfusion injury, vasospasm following subarachnoidhemorrhage, vasospasm following cerebrovascular accident, pleuritis,pericarditis, and the cardiovascular complications of diabetes; (i)dialysis, including pericarditis, due to peritoneal dialysis; (j) gout;and (k) chemical or thermal trauma due to burns, acid, alkali and thelike.

Additional diseases include, for example, equine disorders such aslaminitis and founder's disease.

In another aspect, the present invention provides a method for treatingneuropathic pain, comprising: intrathecally administering to a patientin need thereof a therapeutically effective amount of an A_(2A) agonistof the present invention or a stereoisomer or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method for treatingbiological diseases, comprising: administering a therapeuticallyeffective amount of an anti-pathogenic agent (e.g., an antibiotic,antifungal, or antiviral agent) in combination with an A_(2A) agonist ofthe present invention or a stereoisomer or a pharmaceutically acceptablesalt thereof. If no anti-pathogenic agent is known, the A_(2A) agonistcan be used alone to reduce inflammation, as may occur during infectionwith antibiotic resistant bacteria or certain viruses (e.g., those thatcause SARS, influenza, or Ebola). Optionally, the method furthercomprises administration of a type IV PDE inhibitor. The adenosineA_(2A) receptor agonist can provide adjunctive therapy for treatmentconditions such as the inflammation caused by sepsis, for example, humanuremic syndrome when administered with antibiotics in the treatment ofbio-terrorism weapons, such as anthrax, tularemia, Escherichia coli,Lyme disease, and plague. The adenosine A_(2A) receptor agonists (e.g.,a compound of formula Ia, Ib, 1 or of Table 1) can also provideadjunctive therapy for treatment of lethal pathogenic infections (e.g.,bacterial, fungal, or viral)(e.g., anthrax, tularemia, Escherichia coli,and plague), comprising: administering an anti-pathogenic agent incombination with a compound of the present invention. Also included areyeast and fungal infections with or without anti-yeast or anti-fungalagents.

In another aspect, the invention provides a method to diagnosemyocardial perfusion abnormalities in a subject comprising: (a)parenterally administering to said subject an A_(2A) agonist of thepresent invention or a stereoisomer or a pharmaceutically acceptablesalt thereof; and (b) performing a technique on said subject to detectthe presence of coronary artery stenoses, assess the severity ofcoronary artery stenoses or both.

The compounds of the present invention can be used as a pharmacologicvasodilator agent that can be used with clinical perfusion imagingtechniques, for example, for diagnosing and assessing the extent ofcoronary artery disease. Imaging techniques include planar or singlephoton emission computed tomography (SPECT), gamma camera scintigraphy,positron emission tomography (PET), nuclear magnetic resonance (NMR)imaging, magnetic resonance imaging (MRI), perfusion contrastechocardiography, digital subtraction angiography (DSA), and ultrafastX-ray computed tomography (CINE CT).

The compounds and compositions of the present invention can beadministered as pharmacological stressors and used in conjunction withany one of several noninvasive diagnostic procedures to measure aspectsof myocardial, coronary, and/or ventricular perfusion. Thus, the presentinvention provides a method for perfusion imaging in a subject, such asa human, comprising (1) administering an amount of an A_(2A) agonist ofthe present invention or a stereoisomer or a pharmaceutically acceptablesalt thereof to the subject, and (2) performing a technique on saidsubject to detect and/or determine the presence of an abnormality.Aspects that can be measured include coronary artery stenoses,myocardial dysfunction (e.g., myocardial ischemia, coronary arterydisease, ventricular dysfunction, and differences in blood flow throughdisease-free coronary vessels and/or stenotic coronary vessels),myocardial contractile dysfunction, the presence of regional wall motionabnormalities, the functional significance of stenotic coronary vessels,coronary artery disease, ischemic ventricular dysfunction, andvasodilatory capacity (reserve capacity) of coronary arteries in humans.Radiopharmaceuticals are typically used in diagnostic methods. Theradiopharmaceutical agent may comprise, for example, a radionuclideselected from the group consisting of thallium-201, technetium-99m,nitrogen-13, rubidium-82, iodine-123 and oxygen-15.

The compounds and compositions of the present invention can beadministered as pharmacological stressors to assist with measuringfractional flow reserve (FFR), which is a technique used in coronarycatheterization to measure pressure differences across a coronary arterystenosis.

The diagnostic methods of the present invention typically involve theadministration of one or more A_(2A) agonist of the present invention ora stereoisomer or a pharmaceutically acceptable salt thereof byintravenous infusion in doses which are effective to provide coronaryartery dilation (approximately 0.25-500 mcg/kg/min, or 1-250mcg/kg/min). However, its use in the invasive setting may involve theintracoronary administration of the drug in bolus doses of 0.1-50 mcg.

In another aspect, the adenosine A_(2A) receptor agonist of the presentinvention is administered in combination with a therapeutic agent orprocedure that treats glaucoma or ocular hypertension. Examples of suchagents include alpha agonists (e.g., apraclonidineHCl, brimonidinetartrate), carbonic anhydrase inhibitors (e.g., brinzolamide,dorzolamideHCl, acetazolamide), prostaglandin analogs (e.g., travaprost,bimatoprost, latanoprost), beta blockers (e.g., timolol, betaxolol,levobunolol, metipranolol) and cholinergics (e.g., polocarpineHCl orcarbachol). Examples of procedures that treat glaucoma or ocularhypertension include laser surgery, filtering microsurgery, glaucomaimplants (e.g., shunts) or laser iridotomy.

In another aspect, the present invention provides a compound for use intherapy.

In another aspect, the present invention provides the use of compoundsfor the manufacture of a medicament for the treatment of an indicationrecited herein.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also to beunderstood that each individual element of the embodiments is intendedto be taken individually as its own independent embodiment. Furthermore,any element of an embodiment is meant to be combined with any and allother elements from any embodiment to describe an additional embodiment.

DEFINITIONS

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

“Adenosine A_(2A) receptor agonist” includes compounds that activate theadenosine A_(2A) receptor with a K_(i) of <1 μM as determined by a knownbinding assay. An adenosine A_(2A) receptor agonist may also be crossreactive with other adenosine receptor subtypes (e.g., A₁, A_(2B), andA₃). In one embodiment, the adenosine A_(2A) receptor agonist may beselective for A_(2A) (e.g., at least 2, 10, 50, or 100/1 over anotheradenosine receptor subtype) or may activate/antagonize other receptorswith a greater or lesser affinity than the A_(2A) receptor. In otherembodiments, the adenosine A_(2A) receptor agonist is a compound offormula Ia, Ib, 1 or of Table 1.

“Adenosine A_(2A) receptor associated state” includes those diseases ordisorders which are directly or indirectly implicated in the adenosineA_(2A) receptor pathway. Without being bound by theory, it is thoughtthat administration of an adenosine A_(2A) agonist upregulates thebiological activity of the adenosine A_(2A) receptor by the binding ofthe agonist to the receptor, thereby activating the receptor andtriggering the downstream biological pathway associated with theactivity of the adenosine A_(2A) receptor. Accordingly, an adenosineA_(2A) receptor associated state includes those diseases and disordersdirectly associated with the inactivity or downregulation of theadenosine A_(2A) receptor or the inactivity or downregulation of thebiological pathway associated with the adenosine A_(2A) receptor.Examples of adenosine A_(2A) receptor associated states includeinflammatory disorders and tissue activity, sickle cell disease, sepsis,septic shock, meningitis, peritonitis, arthritis, hemolytic uremicsyndrome, glaucoma and ocular hypertension.

“Reducing ocular hypertension” includes the decrease and/or the completeelimination of ocular hypertension. In one embodiment, the intraocularpressure is reduced by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% to 100% compared to theintraocular pressure prior to treatment.

The compounds herein described may have asymmetric centers, geometriccenters (e.g., double bond), or both. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms, by synthesis fromoptically active starting materials, or through use of chiralauxiliaries. Geometric isomers of olefins, C═N double bonds, or othertypes of double bonds may be present in the compounds described herein,and all such stable isomers are included in the present invention.Specifically, cis and trans geometric isomers of the compounds of thepresent invention may also exist and may be isolated as a mixture ofisomers or as separated isomeric forms. All processes used to preparecompounds of the present invention and intermediates made therein areconsidered to be part of the present invention. All tautomers of shownor described compounds are also considered to be part of the presentinvention.

“Glaucoma” includes a group of eye conditions that lead to damage to theoptic nerve, the nerve that carries visual information from the eye tothe brain. It is an intractable eye disease which exhibits increasedintraocular pressure due to a variety of factors and involves a risk ofleading to blindness. It is known that the incidence rate of glaucomaincreases with age, and the progression of optic nerve injury alsoaccelerates with age. In many cases, damage to the optic nerve is due toincreased pressure in the eye, also known as intraocular pressure (IOP).Glaucoma includes open-angle glaucoma, which includes symptoms such as agradual loss or peripheral vision (also called tunnel vision);angle-closure glaucoma, which includes symptoms such as sudden, severepain in one eye, decreased or cloudy vision, nausea and vomiting,rainbow-like halos around lights, red and/or swollen eye; and congenitalglaucoma, which includes symptoms that are usually noticed when thechild is a few months old, such as cloudiness of the front of the eye,enlargement of one eye or both eyes, red eye and sensitivity to light.

“Ocular hypertension” refers to the condition in which the intraocularpressure is higher than normal, in the absence of optic nerve damage orvisual field loss. One of skill in the art would understand that normalintraocular pressure is between about 10 mmHg and 20 mmHg, where theaverage value of intraocular pressure is 15.5 mmHg with fluctuations ofabout 2.75 mmHg. The language “intraocular pressure” refers to the fluidpressure of the aqueous humor inside the eye.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium. Isotopesof carbon include C-13 and C-14.

Examples of the molecular weight of the compounds of the presentinvention include (a) less than about 500, 550, 600, 650, 700, 750, 800,850, 900, 950, or 1000 grams per mole; (b) less than about 950 grams permole; (c) less than about 850 grams per mole; and, (d) less than about750 grams per mole.

The term “substituted” means that any one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency is not exceeded, andthat the substitution results in a stable compound. When a substituentis keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Ketosubstituents are not present on aromatic moieties.

“Stable” means that the compound is suitable for pharmaceutical use.

The present invention covers stable compounds and thus avoids, unlessotherwise specified, the following bond types: heteroatom-halogen, N—S,O—S, O—O, and S—S.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, and s-pentyl.

When an “ene” terminates a group it indicates the group is attached totwo other groups. For example, methylene refers to a —CH₂— moiety.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆alkenyl includes C₂, C₃, C₄, C₅, andC₆alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynylgroups.

“Alkoxy” includes alkyl, alkenyl, and alkynyl groups covalently linkedto an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy,isopropyloxy, propoxy, t-butyloxy, isobutyloxy, butoxy, and pentoxygroups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

“Cyclic amine” is a hydrocarbon ring wherein one carbon atom of the ringhas been replaced by a nitrogen atom. The cyclic amine can beunsaturated, partially saturated, or fully saturated. The cyclic aminecan also be bicyclic, tricyclic, and polycyclic. Examples of cyclicamine include pyrrolidine and piperdine.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species,such as chloride, bromide, hydroxide, acetate, and sulfate.

The group “C₆H₄” represents a phenylene.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic. Examples of aryl includefluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 memberedmonocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic,and which consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S. If theheteroaryl group is bicyclic or tricyclic, then at least one of the twoor three rings must contain a heteroatom, though both or all three mayeach contain one or more heteroatoms. If the heteroaryl group isbicyclic or tricyclic, then only one of the rings must be aromatic. TheN group may be N, NH, or N-substituent, depending on the chosen ring andif substituents are recited. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroarylring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heteroaryl rings describedherein may be substituted on carbon or on a nitrogen atom if theresulting compound is stable.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

The term “heterocycle” or “heterocyclyl” includes stable 4, 5, 6, 7, 8,9, 10, 11, or 12 membered, (unless the number of members is otherwiserecited), monocyclic, bicyclic, or tricyclic heterocyclic ring that issaturated or partially unsaturated, and which consists of carbon atomsand 1, 2, 3, or 4 heteroatoms independently selected from the groupconsisting of N, O, and S. If the heterocycle is defined by the numberof carbon atoms, then from 1, 2, 3, or 4 of the listed carbon atoms arereplaced by a heteroatom. If the heterocycle is bicyclic or tricyclic,then at least one of the two or three rings must contain a heteroatom,though both or all three may each contain one or more heteroatoms. The Ngroup may be N, NH, or N-substituent, depending on the chosen ring andif substituents are recited. The nitrogen and sulfur heteroatomsoptionally may be oxidized (e.g., S, S(O), S(O)₂, and N—O). Theheterocycle may be attached to its pendant group at any heteroatom orcarbon atom that results in a stable structure. The heterocyclesdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable.

Examples of heterocycles include, but are not limited to,decahydroquinolinyl, imidazolidinyl, imidazolinyl, indolinyl, isatinoyl,methylenedioxyphenyl, morpholinyl, octahydroisoquinolinyl, oxazolidinyl,oxindolyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl,piperonyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,pyrrolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 1-aza-bicyclo[2.2.2]octane,2,5-diaza-bicyclo[2.2.2]octane, and 2,5-diaza-bicyclo[2.2.1]heptane.Also included are fused ring and spiro compounds containing, forexample, the above heterocycles.

“Mammal” and “patient” cover warm blooded mammals that are typicallyunder medical care (e.g., humans and domesticated animals). Examplesinclude feline, canine, equine, bovine, non-human primate, and human, aswell as just human.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, e.g., arresting its development; and/or(c) relieving the disease-state, e.g., causing regression of the diseasestate until a desired endpoint is reached. Treating also includes theamelioration of a symptom of a disease (e.g., lessen the pain ordiscomfort), wherein such amelioration may or may not be directlyaffecting the disease (e.g., cause, transmission, expression, etc.).

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare useful. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to an indication listed herein. “Therapeutically effectiveamount” also includes an amount of the combination of compounds claimedthat is effective to treat the desired indication. The combination ofcompounds can be a synergistic combination. Synergy, as described, forexample, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurswhen the effect of the compounds when administered in combination isgreater than the additive effect of the compounds when administeredalone as a single agent. In general, a synergistic effect is mostclearly demonstrated at sub-optimal concentrations of the compounds.Synergy can be in terms of lower cytotoxicity, increased effect, or someother beneficial effect of the combination compared with the individualcomponents.

Formulations and Dosages

The adenosine A_(2A) receptor agonists of the present invention can beformulated as pharmaceutical compositions and administered to amammalian host, such as a human patient in a variety of forms adapted tothe chosen route of administration, e.g., orally or parenterally, byintravenous (e.g., continuously or bolus), intrathecal, intramuscular,topical, intradermal, intraperitoneal, intraocular, inhalation orsubcutaneous routes. Exemplary pharmaceutical compositions are disclosedin “Remington: The Science and Practice of Pharmacy,” A. Gennaro, ed.,20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptablecarrier/excipient such as an inert diluent or an assimilable ediblecarrier. They may be enclosed in hard or soft shell gelatin capsules,may be compressed into tablets or may be incorporated directly with thefood of the patient's diet. For oral therapeutic administration, theactive compound may be combined with one or more excipients and used inthe form of ingestible tablets, buccal tablets, troches, capsules,elixirs, suspensions, syrups, wafers, and the like. The amount of activecompound in such therapeutically useful compositions is such that aneffective dosage level will be obtained.

The amount of the adenosine A_(2A) receptor agonist of the presentinvention or an active salt or derivative thereof, required for use intreatment will vary not only with the particular compound or saltselected but also with the route of administration, the nature of thecondition being treated, and the age and condition of the patient, andwill ultimately be at the discretion of the attendant physician orclinician. In general, however, a suitable dose will be in the range of(a) about 1.0-100 mg/kg of body weight per day, (b) about 10-75 mg/kg ofbody weight per day, and (c) about 5-20 mg/kg of body weight per day.

For an eye drop, the composition will typically contain an activeingredient at a concentration of generally from 0.000001 to 10% (w/v),also from 0.00001 to 3% (w/v), 0.0001 to 1% (w/v), and 0.001 to 0.1%(w/v) may be instilled to an adult once to several times a day.

For oral administration, the adenosine A_(2A) receptor agonists of thepresent invention may be administered to an adult once or divided intoseveral times at a dose of generally from 0.001 to 5000 mg per day, alsofrom 0.1 to 2500 mg per day, and from 1 to 1000 mg per day.

For a liquid composition (e.g., in a lotion), the concentration ofadenosine A_(2A) receptor agonists of the present invention can be from(a) about 0.1-25 wt % and (b) about 0.5-10 wt %. The concentration in asemi-solid or solid composition such as a gel or a powder can be (a)about 0.1-5 wt % and (b) about 0.5-2.5 wt %.

The adenosine A_(2A) receptor agonists of the present invention can beconveniently administered in unit dosage form; e.g., tablets, caplets,etc., containing (a) about 4-400 mg, (b) about 10-200 mg, and (c) about20-100 mg of active ingredient per unit dosage form.

The adenosine A_(2A) receptor agonists of the present invention can beadministered to achieve peak plasma concentrations of the activecompound of (a) about 0.02-20 μM, (b) about 0.1-10 μM, and (c) about0.5-5 μM. These concentrations may be achieved, for example, by theintravenous injection (e.g., continuously or bolus) of a 0.005-0.5%solution of the active ingredient, or orally administered as a boluscontaining about 4-400 mg of the active ingredient.

When an adenosine A_(2A) receptor agonist of the present invention isadministered in combination with another agent or agents (e.g.,co-administered), then the adenosine A_(2A) receptor agonist of thepresent invention and other agent can be administered simultaneously orin any order. They can be administered as a single pharmaceuticalcomposition or as separate compositions. The administration of theadenosine A_(2A) receptor agonist of the present invention can be priorto the other agent(s), within minutes thereof, or up to hours (e.g., 24or 48) or even days after the administration of the other agent(s). Forexample, the administration of the adenosine A_(2A) receptor agonist ofthe present invention can be within about 24 hours or within about 12hours.

The preventive or therapeutic adenosine A_(2A) receptor agonists of thepresent invention for treating glaucoma or ocular hypertension can beadministered, e.g., either orally or parenterally. Examples of thedosage form include eye drops, ophthalmic ointments, injections,tablets, capsules, granules, powders and the like. In particular, eyedrops are preferred. These can be prepared using any of generally usedtechniques. For example, in the case of eye drops, a desired eye dropcan be prepared by adding the present compound to purified water or abuffer or the like, stifling the mixture, and then adjusting the pH ofthe solution with a pH adjusting agent. Further, an additive which isgenerally used in eye drops can be used as needed. For example,preparation thereof can be carried out using a tonicity agent such assodium chloride or concentrated glycerin, a buffer such as sodiumphosphate, sodium acetate, boric acid, borax or citric acid, asurfactant such as polyoxyethylenesorbitanmonooleate, polyoxyl stearateor polyoxyethylene hydrogenated castor oil, a stabilizer such as sodiumcitrate or sodium ethylenediaminetetraacetate (EDTA), a preservativesuch as benzalkonium chloride or paraben, and the like. The pH of theeye drops is permitted as long as it falls within the range that isacceptable as an ophthalmic preparation, but is preferably in the rangeof from 3 to 8. The ophthalmic ointments can be prepared with agenerally used base such as white petrolatum or liquid paraffin. Also,oral preparations such as tablets, capsules, granules and powders can beprepared by adding an extender such as lactose, crystalline cellulose,starch or vegetable oil, a lubricant such as magnesium stearate or talc,a binder such as hydroxypropyl cellulose or polyvinyl pyrrolidone, adisintegrant such as carboxymethyl cellulose calcium or low-substitutedhydroxypropylmethyl cellulose, a coating agent such ashydroxypropylmethyl cellulose, macrogol or a silicone resin, a filmforming agent such as gelatin film, and the like, as needed.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills or capsules may be coated withgelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The adenosine A_(2A) receptor agonists of the present invention may alsobe administered intravenously (e.g., continuously or bolus) orintraperitoneally by infusion or injection. Solutions of the adenosineA_(2A) receptor agonists of the present invention or their salts can beprepared in water, optionally mixed with a nontoxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, triacetin, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

For topical administration, the adenosine A_(2A) receptor agonists ofthe present invention may be applied in pure form, e.g., when they areliquids. However, it will generally be desirable to administer them tothe skin as compositions or formulations, in combination with adermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings or sprayed onto the affected area usingpump-type or aerosol sprayers.

Examples of useful dermatological compositions which can be used todeliver the adenosine A_(2A) receptor agonists of the present inventionto the skin are known to the art; for example, see Jacquet et al. (U.S.Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S.Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508). Usefuldosages of the compounds of the present invention can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The adenosine A_(2A) receptor agonists of the present invention can alsobe administered by inhalation from an inhaler, insufflator, atomizer orpressurized pack or other means of delivering an aerosol spray.Pressurized packs may comprise a suitable propellant such as carbondioxide or other suitable gas. In case of a pressurized aerosol, thedosage unit may be determined by providing a value to deliver a meteredamount. The inhalers, insufflators, and atomizers are fully described inpharmaceutical reference books such as Remington's PharmaceuticalSciences Volumes 16 (1980) or 18 (1990) Mack Publishing Co.

The desired dose of the adenosine A_(2A) receptor agonists of thepresent invention may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis (e.g., seeU.S. Pat. No. 6,476,060 B2, and J Med Chem 2004, 47, 627). The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in th is field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

One stereoisomer of a compound of the present invention may be a morepotent A_(2A) agonist than its counterpart(s). Thus, stereoisomers areincluded in the present invention. When required, separation of theracemic material can be achieved by HPLC using a chiral column or by aresolution using a resolving agent such as described in Wilen, S. H.Tables of Resolving Agents and Optical Resolutions 1972, 308 or usingenantiomerically pure acids and bases. A chiral compound of the presentinvention may also be directly synthesized using a chiral catalyst or achiral ligand, e.g., Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 orusing other enantio- and diastereo-selective reactions and reagentsknown to one skilled in the art of asymmetric synthesis.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The following examples are representative of the procedures used toprepare the compounds of the present invention.

General Procedure for the Synthesis of N-alkynyl-nicotinamides

N-methyl-N-(prop-2-ynyl)-6-(trifluoromethyl)nicotinamide

N-methylpropargylamine (95%, 1.0 g, 13.75 mmol) and pyridine (5 mL) indry dichloromethane (DCM)(50 mL) were cooled with ice-water.6-(Trifluoromethyl)pyridine-3-carbonyl chloride (97%, 2.83 g, 13.10mmol) was added drop wise with a syringe. The ice bath was removed andthe mixture was stirred at room temperature overnight. DCM (150 mL) wasadded and the mixture was washed with water (3×100 mL). The organicphase was dried with anhydrous MgSO₄, filtered and evaporated todryness, then purified by silica gel column chromatography, eluting withMeOH/DCM (0-2%) to give the product (1.96 g, 70.0% yield), LRMS ESI(M+H+) 243, HPLC rt=5.4 min.

General Procedure for the Synthesis of N-alkynyl-benzamides

N-Cyclobutyl-N-(Prop-2-Ynyl)Benzamide

A mixture of benzoyl chloride (10.90 mL, 94.60 mmol) in ether (250 mL)and water (150 mL) was cooled over ice. Potassium carbonate (14.62 g,105.78 mmol) was added followed by drop wise addition of cyclobutylamine(6.00 mL, 70.28 mmol). The ice was removed and the mixture stirred at25° C. for 48 hours. DCM (350 mL) was added and the mixture washed withwater (2×250 mL). The aqueous was back extracted with DCM (2×150 mL).The combined organic extracts were dried over MgSO₄, filtered andevaporated to dryness under reduced vacuum to afford the crudeN-(cyclobutyl)benzamide (12.14 g, 69.26 mmol, 98.6% yield) which wasused directly in the next reaction.

A solution of the N-(cyclobutyl)benzamide (12.14 g, 69.2621 mmol) in THF(225 mL) was cooled to 5° C. over ice. A solution of n-butyl lithium(1.6 M in hexanes, 54.00 mL, 86.40 mmol) was added drop wise and themixture stirred over ice for 15 minutes. A solution of propargyl bromidein toluene (80% wt., 10.30 mL, 92.47 mmol) was added drop wise. The icewas removed and the mixture stirred for 46 hours. Approximately half ofthe THF was evaporated under reduced vacuum. The mixture was poured overice water (125 mL) and extracted with DCM (3×125 mL). The combinedorganic layers were washed with brine (125 mL), dried over MgSO₄,filtered and evaporated to dryness to afford the crudeN-cyclobutyl-N-(prop-2-yn-1-yl)benzamide (16.33 g, 76.54 mmol). Thecrude material was divided into three equal portions, each of which waspurified by column chromatography (Si=170 g), eluting with EtOAc/hexanes(0-8%). Like fractions were collected and combined to afford thepurified N-cyclobutyl-N-(prop-2-yn-1-yl)benzamide (10.86 g, 50.90 mmol,73.5%), LRMS ESI (M+H+) 214.

General Procedure for the Synthesis of N-alkynyl-acetamides

N-cyclopropyl-2-phenyl-N-(prop-2-ynyl)acetamide

Cyclopropylamine (98%, 1.0 g, 17.17 mmol) and pyridine (5 mL) in dry DCM(50 mL) were cooled with ice-water. 2-Phenylacetyl chloride (98%, 2.58g, 16.36 mmol) was added dropwise with a syringe. The ice bath wasremoved and the mixture was stirred at room temperature overnight. DCM(150 mL) was added and the mixture was washed with water (3×100 mL). Theorganic phase was dried with anhydrous MgSO₄, filtered and evaporated todryness, then used in the next step.

Sodium hydride (60% in mineral oil, 706 mg, 17.65 mmol) was washed withdry ether (2×20 mL) and then suspended in dry THF (30 mL) and cooledwith ice-water. Crude N-cyclopropyl-2-phenylacetamide from the last stepin THF (5 mL) was added dropwise at 5° C. to the sodium hydridesuspension. The reaction mixture was stirred at 5° C. for 20 min. Asolution of propargyl bromide in toluene (80% wt., 2.68 mL, 24.06 mmol)was added dropwise with a syringe. The ice bath was removed and themixture was stirred at room temperature overnight. The mixture waspoured into ice-water (100 mL) and extracted with DCM (3×100 mL). Theorganic phases were combined and washed with brine (2×50 mL), dried withanhydrous MgSO₄, filtered and evaporated to dryness, then purified bysilica gel column chromatography, eluting with MeOH/DCM (0-2%) to givethe title compound (2.05 g, 58.8% yield), LRMS ESI (M+H⁺) 214.

General Procedure for the Synthesis of N-benzyl-N-alkynyl-carboxamides

N-(4-Methoxybenzyl)-N-(prop-2-ynyl)cyclopropanecarboxamide

4-Methoxybenzylamine (98%, 4.0 g, 16.11 mmol) and pyridine (5 mL) in dryDCM (50 mL) were cooled with ice-water. Cyclopropanecarbonyl chloride(98%, 1.57 mL, 16.96 mmol) was added dropwise with a syringe. The icebath was removed and the mixture was stirred at room temperatureovernight. DCM (150 mL) was added and the mixture was washed with water(3×100 mL). The organic phase was dried with anhydrous MgSO₄, filteredand evaporated to dryness, then used in the next step.

Sodium hydride (60% in mineral oil, 709 mg, 17.72 mmol) was washed withdry ether (2×20 mL) and then suspended in dry THF (30 mL) and cooledwith ice-water. Crude N-(4-methoxybenzyl)cyclopropanecarboxamide fromlast step in THF (5 mL) was added dropwise at 5° C. to the sodiumhydride suspension. The reaction mixture was stirred at 5° C. for 20min. A solution of propargyl bromide in toluene (80% wt., 2.69 mL, 24.17mmol) was added dropwise with a syringe. The ice bath was removed andthe mixture was stirred at room temperature overnight. The mixture waspoured into ice-water (100 mL) and extracted with DCM (3×100 mL). Theorganic phases were combined and washed with brine (2×50 mL), dried withanhydrous MgSO₄, filtered and evaporated to dryness, then purified bysilica gel column chromatography, eluting with MeOH/DCM (0-2%) to givethe product (2.43 g, 62.0% yield), LRMS ESI (M+H⁺) 244.

General Procedure for the Synthesis of 2-alkynyl adenosine-5′-uronamides

To a solution of N-methyl 2-iodoadenosine-5′-uronamide (0.45mmol)(structure A above) in freshly degassed THF (35 mL) was addedpotassium carbonate (1.9 mmol), copper(I) iodide (0.21 mmol), palladium(0) tetrakistriphenylphosphine (0.057 mmol) and the corresponding alkyne(0.85 mmol)(e.g., for Example 1,N-methyl-N-(prop-2-yn-1-yl)-6-(trifluoromethyl)nicotinamide, structure Babove). The mixture was stirred at room temperature under an inertatmosphere for 20 to 24 h. Silica bound Pd(II) scavenger Si-Thiol (225mg) and Pd(0) scavenger Si-TAAcOH (475 mg) were added and stirringcontinued a further 24 h. The suspension was filtered and the resultingsolution evaporated to dryness. The crude was purified by chromatographyon a 43 g column (2.1 cm×30 cm) of 40-60 μM silica gel eluting with agradient of DCM/MeOH to afford the pure product.

Example 1 N-Methyl2-(3-{N-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]formamido}prop-1-yn-1-yl)adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (98mg) and N-methyl-N-(prop-2-yn-1-yl)-6-(trifluoromethyl)nicotinamide gavethe title compound as an off-white solid: yield 29 mg, 23%. LRMS ESI(M+H⁺) 535.35. HPLC rt=4.3 min.

Example 2 N-Cyclopropyl2-(3-{N-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]formamido}prop-1-yn-1-yl)adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-cyclopropyl2-iodoadenosine-5′-uronamide (98 mg) andN-methyl-N-(prop-2-yn-1-yl)-6-(trifluoromethyl)nicotinamide gave thetitle compound as an off-white solid: yield 52 mg, 42%. LRMS ESI (M+H⁺)561.40. HPLC rt=4.8 min.

Example 3 N-Cyclopropyl2-{3-[N-(cyclopropylmethyl)benzamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-cyclopropyl2-iodoadenosine-5′-uronamide (63 mg) andN-(cyclopropylmethyl)-N-(prop-2-yn-1-yl)benzamide gave the titlecompound as a brown solid: yield 32 mg, 42%. LRMS ESI (M+H⁺) 532.40.HPLC rt=6.7 min.

Example 4 N-Cyclopropyl2-{3-[N-(cyclobutyl)benzamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-cyclopropyl2-iodoadenosine-5′-uronamide (73 mg) andN-cyclobutyl-N-(prop-2-yn-1-yl)benzamide gave the title compound as abrown solid: yield 35 mg, 40%. LRMS ESI (M+H⁺) 532.40. HPLC rt=6.9 min.

Example 5 N-Cyclopropyl2-{3-[benzamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-cyclopropyl2-iodoadenosine-5′-uronamide (58 mg) and N-(prop-2-yn-1-yl)benzamidegave the title compound as a brown solid: yield 21 mg, 45%. LRMS ESI(M+H⁺) 478.30. HPLC rt=4.2 min.

Example 6 N-Methyl2-{3-[N-methyl-1-(6-fluoropyridin-3-yl)formamido]prop-1-yn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (97mg) and 6-fluoro-N-methyl-N-(prop-2-yn-1-yl)nicotinamide gave the titlecompound as an off-white solid: yield 15 mg, 13%. LRMS ESI (M+H⁺)485.35. HPLC rt=2.8 min.

Example 7 N-Cyclopropyl2-{3-[N-methyl-1-(6-fluoropyridin-3-yl)formamido]prop-1-yn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-cyclopropyl2-iodoadenosine-5′-uronamide (97 mg) and6-fluoro-N-methyl-N-(prop-2-yn-1-yl)nicotinamide gave the title compoundas an off-white solid: yield 30 mg, 27%. LRMS ESI (M+H⁺) 511.40. HPLCrt=3.2 min.

Example 8 N-Methyl2-{3-[N-(cyclobutyl)benzamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide(191 mg) and N-cyclobutyl-N-(prop-2-yn-1-yl)benzamide gave the titlecompound as a brown solid: yield 124 mg, 54%. LRMS ESI (M+H⁺) 506.35.HPLC rt=6.6 min.

Example 9 N-Methyl2-{3-[N-methylnicotinamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide(100 mg) and N-methyl-N-(prop-2-yn-1-yl)nicotinamide gave the titlecompound as a brown solid: yield 28 mg, 25%. LRMS ESI (M+H⁺) 467.30.HPLC rt=2.5 min.

Example 10 N-Methyl2-{3-[N-methylisonicotinamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (94mg) and N-methyl-N-(prop-2-yn-1-yl)isonicotinamide gave the titlecompound as a brown solid: yield 26 mg, 25%. LRMS ESI (M+H⁺) 467.30.HPLC rt=2.3 min.

Example 11 N-Methyl2-{3-[6-fluoro-N-(2-methoxyethyl)nicotinamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (80mg) and 6-fluoro-N-(2-methoxyethyl)-N-(prop-2-yn-1-yl)nicotinamide gavethe title compound as a brown solid: yield 50 mg, 50%. LRMS ESI (M+H⁺)529.35. HPLC rt=3.3 min.

Example 12 N-Methyl2-{3-[N-(2-methoxyethyl)thiophene-2-carboxamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (78mg) and N-(2-methoxyethyl)-N-(prop-2-yn-1-yl)thiophene-2-carboxamidegave the title compound as a brown solid: yield 44 mg, 46%. LRMS ESI(M+H⁺) 516.30. HPLC rt=4.4 min.

Example 13 N-Methyl2-{3-[N-methylbenzamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (89mg) and N-methyl-N-(prop-2-yn-1-yl)benzamide gave the title compound asa brown solid: yield 33 mg, 33%. LRMS ESI (M+H⁺) 466.30. HPLC rt=4.1min.

Example 14 N-Methyl2-{3-[N-(2-methoxyethyl)benzamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (94mg) and N-(2-methoxyethyl)-N-(prop-2-yn-1-yl)benzamide gave the titlecompound as a brown solid: yield 91 mg, 79%. LRMS ESI (M+H⁺) 510.35.HPLC rt=4.7 min.

Example 15 N-Methyl2-{3-[4-fluoro-N-methylbenzamido]propyn-1-yl}adenosine-5′-uronamide

Using the general procedure for the synthesis of 2-alkynyladenosine-5′-uronamides above, N-methyl 2-iodoadenosine-5′-uronamide (99mg) and 4-fluoro-N-methyl-N-(prop-2-yn-1-yl)benzamide gave the titlecompound as a brown solid: yield 59 mg, 52%. LRMS ESI (M+H⁺) 484.30.HPLC rt=4.4 min.

Examples 16-36 in Table 1 are compounds of the present invention thatwere synthesized using the methods described above from thecorresponding iodo-uronamide and 2-substituted-propyn-1-yl. The starting2-substituted-propyn-1-yl groups were prepared according to the generalprocedures provided above.

In Table 1, M.S. is LRMS ESI (M+H⁺). General HPLC Conditions fordetermining purity: Gradient of 40% methanol (0.1% Formic acid)/60%water (0.1% Formic acid) to 80% methanol (0.1% Formic acid)/20% water(0.1% Formic acid) over 15 minutes. UV at 270 nm. Retention times (RT)are shown below.

The binding of A_(2A)Ki values for tested compounds is provided inTable 1. The Ki values were obtained using the methodology described byMurphree et al. in Mol Pharmacol 2002, 61, 455-62.

-   -   +++>50 nM    -   ++1-50 nM    -   +<1 nM

TABLE 1 LRMS ESI (M + H+) Ret. Time Ex # Structure (RT) Ki 1.

535.40 4.3 min + 2.

561.40 4.8 min + 3.

532.40 6.7 min + 4.

532.40 6.9 min + 5.

478.30 4.2 min ++ 6.

485.35 2.9 min + 7.

511.40 3.2 min ++ 8.

506.35 6.6 min + 9.

467.30 2.5 min ++ 10.

467.30 2.3 min ++ 11.

529.35 3.3 min + 12.

516.30 4.4 min + 13.

466.30 4.1 min + 14.

510.35 4.7 min + 15.

484.30 4.4 min + 16.

532.45 7.5 min ++ 17.

536.40 7.2 min ++ 18.

562.45 7.4 min + 19.

524.40 8.2 min + 20.

524.35 8.2 min + 21.

554.35 8.3 min + 22.

527.40 6.2 min + 23.

492.40 6.9 min +++ 24.

553.40 6.3 min + 25.

518.45 7.0 min + 26.

541.40 6.5 min + 27.

520.50 7.6 min ++ 28.

549.45 6.3 min + 29.

514.25 7.3 min + 30.

540.30 8.9 min + 31.

520.30 8.5 min + 32.

508.30 8.3 min + 33.

491.25 6.6 min + 34.

548.25 8.4 min ++ 35.

499.40 5.3 min + 36.

550.45 7.7 min ++

Examples 1-33 of Table 2 are additional representative examples of thepresent invention. These examples can be synthesized using the methodsdescribed above by coupling the correspondingmethyl/ethyl/cyclopropyl-uronamide and corresponding2-substituted-propyn-1-yl. The starting 2-substituted-propyn-1-yl groupscan be prepared according to the general procedures provided above.

TABLE 2 Ex. # Structure 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

All references listed herein are individually incorporated in theirentirety by reference.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled) 11.(canceled)
 12. (canceled)
 13. (canceled)
 14. (canceled)
 15. (canceled)16. (canceled)
 17. (canceled)
 18. (canceled)
 19. (canceled) 20.(canceled)
 21. (canceled)
 22. (canceled)
 23. (canceled)
 24. A compoundor a stereoisomer or pharmaceutically acceptable salt thereof, whereinthe compound is a compound selected from Tables 1 and 2 as follows:TABLE 1 Ex # Structure 1

6

8

9

10

13

15

19

20

21

29

30

31

TABLE 2 Ex. # Structure 1

2

4

5

6

10

11

27

29

32


25. A compound of claim 24, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein the compound is a compound selectedfrom Tables 1 and 2 as follows: TABLE 1 Ex # Structure 1

6

8

20

21

TABLE 2 Ex. # Structure 1

4

6

27

29


26. A compound of claim 25, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein the compound is compound 1 fromTable
 1. 27. A compound of claim 25, or a stereoisomer orpharmaceutically acceptable salt thereof, wherein the compound iscompound 6 from Table
 1. 28. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 8 from Table
 1. 29. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 20 from Table
 1. 30. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 21 from Table
 1. 31. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 1 from Table
 2. 32. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 4 from Table
 2. 33. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 6 from Table
 2. 34. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 27 from Table
 2. 35. A compound of claim 25, or a stereoisomeror pharmaceutically acceptable salt thereof, wherein the compound iscompound 29 from Table
 2. 36. A pharmaceutical composition, comprising:a therapeutically effective amount of a compound of claim 24 or astereoisomer or pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 37. A method for treating anadenosine A_(2A) receptor associated state in a subject, comprising:administering to the subject an effective amount of a compound of claim24 or a stereoisomer or pharmaceutically acceptable salt thereof. 38.The method of claim 37, wherein the adenosine A_(2A) receptor associatedstate is selected from an autoimmune stimulation, inflammation, allergicdiseases, skin diseases, infectious diseases, wasting diseases, organtransplantation, tissue or cell transplantation, neuropathic pain, openwounds, adverse effects from drug therapy, a cardiovascular condition,ischemia-reperfusion injury, dialysis, gout, chemical trauma, thermaltrauma, diabetic nephropathy, sickle cell disease, laminitis, founder'sdisease, glaucoma, and ocular hypertension, spinal injury, myocardialinfarction, acute myocardial infarction.
 39. The method of claim 37,wherein the adenosine A_(2A) receptor associated state is selected from:arthritis, Crohn's disease, chronic obstructive pulmonary disease,sepsis, inflammatory bowel disease, glaucoma, ocular hypertension,diabetic nephropathy, tissue or cell transplantation,
 40. The method ofclaim 37, wherein the adenosine A_(2A) receptor associated state iscaused by Shiga toxin, Clostridium difficile, or Clostridium difficiletoxin A-induced condition.
 41. A method of diagnosing myocardialperfusion abnormalities in a mammal, comprising: a. parenterallyadministering to the mammal a unit dose of a compound of claim 24; and,b. performing a technique on the mammal to detect the presence ofcoronary artery stenosis, assess the severity of coronary arterystenosis, or a combination thereof.
 42. A method of reducing interocularpressure in a subject, comprising: administering to the subject aneffective amount of a compound of claim 24 or a stereoisomer orpharmaceutically acceptable salt thereof, such that the intraocularpressure is reduced.